Journal articles: 'LDL transport'

1

Rutledge, J. C. "Temperature and hydrostatic pressure-dependent pathways of low-density lipoprotein transport across microvascular barrier." American Journal of Physiology-Heart and Circulatory Physiology 262, no. 1 (January 1, 1992): H234—H245. http://dx.doi.org/10.1152/ajpheart.1992.262.1.h234.

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To further investigate the chemical and physical nature of low-density lipoprotein (LDL) transport pathways across intact microvessels, the effect of changes in temperature and microvessel hydrostatic pressure were measured in individually perfused postcapillary vessels within frog mesenteric vascular beds. LDL microvessel transport was measured at two microvessel temperature ranges (18-21 degrees C and 4-6 degrees C) and compared with transport of fluorescein, a small solute. Also, LDL transport was measured at a series of hydrostatic pressures (3-20 cmH2O) at microvessel temperatures of 18-21 degrees C and 4-6 degrees C to determine whether LDL transport was coupled to water flow, which would be evidence for hydraulic pathways of solute transport across the microvascular barrier. Quantitative fluorescence microscopy was employed to determine apparent solute permeability coefficients (Ps) under the various temperature and hydrostatic pressure conditions studied. The ratio of Ps fluorescein 18-21 degrees C/4-6 degrees C [1.6 +/- 0.3 (SD)] indicated that fluorescein was freely diffusible across the microvascular barrier through water-filled pathways as transport was inversely proportional to temperature-dependent changes in viscosity. The larger ratio for LDL (Ps LDL 18-21/4-6 degrees C = 9.5 +/- 8.1) than for fluorescein cannot be explained by LDL transport through fixed hydraulic pathways alone and suggests additional or alternate LDL transport mechanisms. In addition, Ps LDL increased as microvessel hydrostatic pressure increased at microvessel temperatures of 18-21 degrees C but not at 4-6 degrees C. Coupling of LDL transport to water flow at the high microvessel temperature range, but not at the low range, indicated the presence of a hydraulic transport pathway that was effectively absent when the microvessel was cooled. These results demonstrated a highly temperature and hydrostatic pressure-dependent LDL pathway that is consistent with a dynamic porous extracellular or transcellular mechanism of LDL transport.

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von Eckardstein, Arnold. "LDL Contributes to Reverse Cholesterol Transport." Circulation Research 127, no. 6 (August 28, 2020): 793–95. http://dx.doi.org/10.1161/circresaha.120.317721.

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Kakava, Sofia, Eveline Schlumpf, Grigorios Panteloglou, Flavia Tellenbach, Arnold von Eckardstein, and Jerome Robert. "Brain Endothelial Cells in Contrary to the Aortic Do Not Transport but Degrade Low-Density Lipoproteins via Both LDLR and ALK1." Cells 11, no. 19 (September 28, 2022): 3044. http://dx.doi.org/10.3390/cells11193044.

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The transport of low-density lipoprotein (LDL) through the endothelium is a key step in the development of atherosclerosis, but it is notorious that phenotypic differences exist between endothelial cells originating from different vascular beds. Endothelial cells forming the blood–brain barrier restrict paracellular and transcellular passage of plasma proteins. Here, we systematically compared brain versus aortic endothelial cells towards their interaction with LDL and the role of proteins known to regulate the uptake of LDL by endothelial cells. Both brain endothelial cells and aortic endothelial cells bind and internalize LDL. However, whereas aortic endothelial cells degrade very small amounts of LDL and transcytose the majority, brain endothelial cells degrade but do not transport LDL. Using RNA interference (siRNA), we found that the LDLR–clathrin pathway leads to LDL degradation in either endothelial cell type. Both loss- and gain-of-function experiments showed that ALK1, which promotes transcellular LDL transport in aortic endothelial cells, also limits LDL degradation in brain endothelial cells. SR-BI and caveolin-1, which promote LDL uptake and transport into aortic endothelial cells, limit neither binding nor association of LDL to brain endothelial cells. Together, these results indicate distinct LDL trafficking by brain microvascular endothelial cells and aortic endothelial cells.

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Cancel, Limary M., Andrew Fitting, and John M. Tarbell. "In vitro study of LDL transport under pressurized (convective) conditions." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 1 (July 2007): H126—H132. http://dx.doi.org/10.1152/ajpheart.01188.2006.

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It is difficult to assess the transport pathways that carry low-density lipoprotein (LDL) into the artery wall in vivo, and there has been no previous in vitro study that has examined transendothelial transport under physiologically relevant pressurized (convective) conditions. Therefore, we measured water, albumin, and LDL fluxes across bovine aortic endothelial cell (BAEC) monolayers in vitro and determined the relative contributions of vesicles, paracellular transport through “breaks” in the tight junction, and “leaky” junctions associated with dying or dividing cells. Our results show that leaky junctions are the dominant pathway for LDL transport (>90%) under convective conditions and that albumin also has a significant component of transport through leaky junctions (44%). Transcellular transport of LDL by receptor-mediated processes makes a minor contribution (<10%) to overall transport under convective conditions.

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Li, Xiaoyin, Xiao Liu, Peng Zhang, Chenglong Feng, Anqiang Sun, Hongyan Kang, Xiaoyan Deng, and Yubo Fan. "Numerical simulation of haemodynamics and low-density lipoprotein transport in the rabbit aorta and their correlation with atherosclerotic plaque thickness." Journal of The Royal Society Interface 14, no. 129 (April 2017): 20170140. http://dx.doi.org/10.1098/rsif.2017.0140.

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Two mechanisms of shear stress and mass transport have been recognized to play an important role in the development of localized atherosclerosis. However, their relationship and roles in atherogenesis are still obscure. It is necessary to investigate quantitatively the correlation among low-density lipoproteins (LDL) transport, haemodynamic parameters and plaque thickness. We simulated blood flow and LDL transport in rabbit aorta using computational fluid dynamics and evaluated plaque thickness in the aorta of a high-fat-diet rabbit. The numerical results show that regions with high luminal LDL concentration tend to have severely negative haemodynamic environments (HEs). However, for regions with moderately and slightly high luminal LDL concentration, the relationship between LDL concentration and the above haemodynamic indicators is not clear cut. Point-by-point correlation with experimental results indicates that severe atherosclerotic plaque corresponds to high LDL concentration and seriously negative HEs, less severe atherosclerotic plaque is related to either moderately high LDL concentration or moderately negative HEs, and there is almost no atherosclerotic plaque in regions with both low LDL concentration and positive HEs. In conclusion, LDL distribution is closely linked to blood flow transport, and the synergetic effects of luminal surface LDL concentration and wall shear stress-based haemodynamic indicators may determine plaque thickness.

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Liscum, L., R. M. Ruggiero, and J. R. Faust. "The intracellular transport of low density lipoprotein-derived cholesterol is defective in Niemann-Pick type C fibroblasts." Journal of Cell Biology 108, no. 5 (May 1, 1989): 1625–36. http://dx.doi.org/10.1083/jcb.108.5.1625.

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Niemann-Pick disease type C (NPC) is characterized by substantial intracellular accumulation of unesterified cholesterol. The accumulation of unesterified cholesterol in NPC fibroblasts cultured with low density lipoprotein (LDL) appears to result from the inability of LDL to stimulate cholesterol esterification in addition to impaired LDL-mediated downregulation of LDL receptor activity and cellular cholesterol synthesis. Although a defect in cholesterol transport in NPC cells has been inferred from previous studies, no experiments have been reported that measure the intracellular movement of LDL-cholesterol specifically. We have used four approaches to assess intracellular cholesterol transport in normal and NPC cells and have determined the following: (a) mevinolin-inhibited NPC cells are defective in using LDL-cholesterol for growth. However, exogenously added mevalonate restores cell growth equally in normal and NPC cells; (b) the transport of LDL-derived [3H]cholesterol to the plasma membrane is slower in NPC cells, while the rate of appearance of [3H]acetate-derived, endogenously synthesized [3H]cholesterol at the plasma membrane is the same for normal and NPC cells; (c) in NPC cells, LDL-derived [3H]cholesterol accumulates in lysosomes to higher levels than normal, resulting in defective movement to other cell membranes; and (d) incubation of cells with LDL causes an increase in cholesterol content of NPC lysosomes that is threefold greater than that observed in normal lysosomes. Our results indicate that a cholesterol transport defect exists in NPC that is specific for LDL-derived cholesterol.

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Pfisterer, Simon G., Johan Peränen, and Elina Ikonen. "LDL–cholesterol transport to the endoplasmic reticulum." Current Opinion in Lipidology 27, no. 3 (June 2016): 282–87. http://dx.doi.org/10.1097/mol.0000000000000292.

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Kang, Hongyan, Jiali Yang, Weichen Zhang, Jinyan Lu, Xuejiao Ma, Anqiang Sun, and Xiaoyan Deng. "Effect of endothelial glycocalyx on water and LDL transport through the rat abdominal aorta." American Journal of Physiology-Heart and Circulatory Physiology 320, no. 4 (April 1, 2021): H1724—H1737. http://dx.doi.org/10.1152/ajpheart.00861.2020.

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A 42% degradation of the endothelial glycocalyx by hyaluronidase of the isolated rat abdominal aorta facilitated water and LDL transport across the vessel wall, suggesting endothelial glycocalyx as a transport barrier. A 24-h shear exposure increased LDL mean maximum infiltration distance, and enhanced EC apoptosis, which could be both inhibited by hyaluronidase treatment, suggesting endothelial glycocalyx may also act as a mechanosensor of shear to regulate EC apoptosis, thus affecting leaky junctions and regulating LDL transport.

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Skeggs, Josephine W., and Richard E. Morton. "LDL and HDL enriched in triglyceride promote abnormal cholesterol transport." Journal of Lipid Research 43, no. 8 (August 2002): 1264–74. http://dx.doi.org/10.1194/jlr.m100431-jlr200.

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Hypertriglyceridemia induces multiple changes in lipoprotein composition. Here we investigate how one of these modifications, triglyceride (TG) enrichment, affects HDL and LDL function when this alteration occurs under conditions in which more polar components can naturally re-equilibrate. TG-enriched lipoproteins were produced by co-incubating VLDL, LDL, and HDL with cholesteryl ester (CE) transfer protein. The resulting 2.5-fold increase in TG/CE ratio did not measurably alter the apoprotein composition of LDL or HDL, or modify LDL size. HDL mean diameter increased slightly from 9.1 to 9.4 nm. Modified LDL was internalized by fibroblasts normally, but its protein was degraded much less efficiently. This likely reflects an aberrant apolipoprotein B (apoB) conformation, as suggested by its resistance to V8 protease digestion and altered LDL electrophoretic mobility. TG-enriched LDL ineffectively down-regulated cholesterol biosynthesis compared with control LDL at the same protein concentration, but was equivalent in sterol regulation when compared on a cholesterol basis. TG-enriched HDL promoted greater net cholesterol efflux from cholesterol-loaded J774 cells. However, cholesterol associated with TG-enriched HDL was inefficiently esterified by lecithin:cholesterol acyltransferase, and TG-enriched HDLs were poor donors of CE to HepG2 hepatocytes by selective uptake.We conclude that TG-enrichment, in the absence of other significant alterations in lipoprotein composition, is sufficient to alter both cholesterol delivery and removal mechanisms. Some of these abnormalities may contribute to increased coronary disease in hypertriglyceridemia.

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10

Jensen, Jan Skov, Bo Feldt-Rasmussen, Knut Borch-Johnsen, Kurt Svarre Jensen, and Børge Grønne Nordestgaard. "Increased Transvascular Lipoprotein Transport in Diabetes: Association with Albuminuria and Systolic Hypertension." Journal of Clinical Endocrinology & Metabolism 90, no. 8 (August 1, 2005): 4441–45. http://dx.doi.org/10.1210/jc.2004-2420.

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Abstract Context: Diabetes is associated with a highly increased risk of atherosclerosis, especially if hypertension or albuminuria is present. Objective: We hypothesized that the increased transvascular lipoprotein transport in diabetes may be further accelerated if hypertension or albuminuria is present, possibly explaining increased intimal lipoprotein accumulation and thus atherosclerosis. Design: The study was cross-sectional and was performed in 1999–2002. Setting: The study took place in the referral center. Patients: The patients included 60 with diabetes mellitus (27 with type 1 diabetes and 33 with type 2 diabetes) and 42 healthy controls. All were randomly recruited. Main Outcome Measure: We used an in vivo method for measurement of transvascular transport of low-density lipoprotein (LDL). Autologous 131I-LDL was reinjected iv, and the 1-h fractional escape rate was taken as an index of transvascular transport. Results: Transvascular LDL transport was 1.8 (1.6–2.0), 2.3 (2.0–2.6), and 2.6 (1.3–4.0)%/[h × (liter/m2)] in healthy controls, diabetic controls, and diabetes patients with systolic hypertension or albuminuria, respectively (P = 0.013; F = 4.5; df =2; ANOVA). These differences most likely were not caused by altered hepatic LDL receptor expression, glycosylation of LDL, small LDL size, or medicine use. Conclusions: Transvascular LDL transport is increased in patients with diabetes mellitus, especially if systolic hypertension or albuminuria is present. Accordingly, lipoprotein flux into the arterial wall could be increased in these patients, possibly explaining accelerated development of atherosclerosis.

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11

Fragoso, Yara Dadalti, and Andrew Joseph Brown. "In vivo metabolism of alpha-tocopherol in lipoproteins and liver: studies on rabbits in response to acute cholesterol loading." Sao Paulo Medical Journal 116, no. 4 (July 1998): 1753–59. http://dx.doi.org/10.1590/s1516-31801998000400003.

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OBJECTIVE: To investigate the transport of alpha-tocopherol in lipoproteins of rabbits under normal diet and under acute loading of cholesterol. DESIGN: Two New Zealand White rabbits were fed 14C-alpha-tocopherol acetate in a single oral dose and the recovery of radiolabel in lipoproteins and plasma was monitored. Low density lipoprotein (LDL) from these animals was obtained and labeled with [3H] cholesteryl ester. Three other rabbits were injected with this double-labeled LDL in the native form; while three other animals received this LDL in the acetylated form. RESULTS: Plasma clearance, liver uptake and levels of radiolabel in high density lipoprotein (HDL) of animals injected with 14C[3H]acetyl LDL were significantly higher than those in animals injected with 14C[3H]native LDL. Larger particles of HDL, rich in apolipoprotein E (apoE) carried significantly higher levels of both labels in rabbits injected with acetylated LDL. CONCLUSION: These results provide evidence for in vivo mechanisms of "reverse alpha-tocopherol transport", analogous to "reverse cholesterol transport".

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12

Velagapudi, Srividya, Mustafa Yalcinkaya, Antonio Piemontese, Roger Meier, Simon Flyvbjerg Nørrelykke, Damir Perisa, Andrzej Rzepiela, et al. "VEGF-A Regulates Cellular Localization of SR-BI as Well as Transendothelial Transport of HDL but Not LDL." Arteriosclerosis, Thrombosis, and Vascular Biology 37, no. 5 (May 2017): 794–803. http://dx.doi.org/10.1161/atvbaha.117.309284.

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Objective— Low- and high-density lipoproteins (LDL and HDL) must pass the endothelial layer to exert pro- and antiatherogenic activities, respectively, within the vascular wall. However, the rate-limiting factors that mediate transendothelial transport of lipoproteins are yet little known. Therefore, we performed a high-throughput screen with kinase drug inhibitors to identify modulators of transendothelial LDL and HDL transport. Approach and Results— Microscopy-based high-content screening was performed by incubating human aortic endothelial cells with 141 kinase-inhibiting drugs and fluorescent-labeled LDL or HDL. Inhibitors of vascular endothelial growth factor (VEGF) receptors (VEGFR) significantly decreased the uptake of HDL but not LDL. Silencing of VEGF receptor 2 significantly decreased cellular binding, association, and transendothelial transport of 125 I-HDL but not 125 I-LDL. RNA interference with VEGF receptor 1 or VEGF receptor 3 had no effect. Binding, uptake, and transport of HDL but not LDL were strongly reduced in the absence of VEGF-A from the cell culture medium and were restored by the addition of VEGF-A. The restoring effect of VEGF-A on endothelial binding, uptake, and transport of HDL was abrogated by pharmacological inhibition of phosphatidyl-inositol 3 kinase/protein kinase B or p38 mitogen-activated protein kinase, as well as silencing of scavenger receptor BI. Moreover, the presence of VEGF-A was found to be a prerequisite for the localization of scavenger receptor BI in the plasma membrane of endothelial cells. Conclusions— The identification of VEGF as a regulatory factor of transendothelial transport of HDL but not LDL supports the concept that the endothelium is a specific and, hence, druggable barrier for the entry of lipoproteins into the vascular wall.

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13

Stangeby, D. Kim, and C. Ross Ethier. "Computational Analysis of Coupled Blood-Wall Arterial LDL Transport." Journal of Biomechanical Engineering 124, no. 1 (September 17, 2001): 1–8. http://dx.doi.org/10.1115/1.1427041.

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The transport of macromolecules, such as low density lipoproteins (LDLs), across the artery wall and their accumulation in the wall is a key step in atherogenesis. Our objective was to model fluid flow within both the lumen and wall of a constricted, axisymmetric tube simulating a stenosed artery, and to then use this flow pattern to study LDL mass transport from the blood to the artery wall. Coupled analysis of lumenal blood flow and transmural fluid flow was achieved through the solution of Brinkman’s model, which is an extension of the Navier-Stokes equations for porous media. This coupled approach offers advantages over traditional analyses of this problem, which have used possibly unrealistic boundary conditions at the blood-wall interface; instead, we prescribe a more natural pressure boundary condition at the adventitial vasa vasorum, and allow variations in wall permeability due to the occurrence of plaque. Numerical complications due to the convection dominated mass transport process (low LDL diffusivity) are handled by the streamline upwind/Petrov-Galerkin (SUPG) finite element method. This new fluid-plus-porous-wall method was implemented for conditions typical of LDL transport in a stenosed artery with a 75 percent area reduction (Peclet number=2×108). The results show an elevated LDL concentration at the downstream side of the stenosis. For the higher Darcian wall permeability thought to occur in regions containing atheromatous lesions, this leads to an increased transendothelial LDL flux downstream of the stenosis. Increased transmural filtration in such regions, when coupled with a concentration-dependent endothelial permeability to LDL, could be an important contributor to LDL infiltration into the arterial wall. Experimental work is needed to confirm these results.

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Rutledge, J. C., F. E. Curry, P. Blanche, and R. M. Krauss. "Solvent drag of LDL across mammalian endothelial barriers with increased permeability." American Journal of Physiology-Heart and Circulatory Physiology 268, no. 5 (May 1, 1995): H1982—H1991. http://dx.doi.org/10.1152/ajpheart.1995.268.5.h1982.

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We investigated the mechanisms of hamster low-density lipoprotein (LDL) transport across the endothelial barrier in individually perfused venular microvessels in hamster mesentery. These experiments are the first to use microperfusion techniques and quantitative fluorescence microscopy to investigate LDL transport across mammalian microvessel endothelium. The apparent permeability coefficient for hamster LDL, PsLDL, rose from 2.7 x 10(-7) cm/s at control to 23.2 x 10(-7) cm/s at the peak of the biphasic increase in microvessel permeability after exposure of the vessels to 100 microM histamine. Close to the peak, PsLDL rose 1.85 x 10(-7) cm/s for every centimeter of H2O increase in hydrostatic pressure. Thus, at a mean pressure of 11.3 cmH2O, 90% of the LDL flux was coupled to transendothelial water flow by a solvent drag mechanism. The corresponding solvent drag reflection coefficient for hamster LDL was estimated to be approximately 0.8. These results are consistent with sieving hamster LDL (effective radius 14.9 nm) through equivalent pores of approximately 22 nm radius. Similar results were found with human LDL (effective radius 13.2 nm) in hamster microvessels. The results provide a bridge between studies of LDL transport across cultured endothelial barriers, where high diffusive permeability coefficients to LDL may obscure the contributions of solvent drag, and studies in whole animals, where the consequences of sieving of LDL at the vessel wall, even in the high permeability state, have not received much attention.

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Weinbaum, Sheldon, and Shu Chien. "Lipid Transport Aspects of Atherogenesis." Journal of Biomechanical Engineering 115, no. 4B (November 1, 1993): 602–10. http://dx.doi.org/10.1115/1.2895547.

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In this review we shall examine the current understanding of events that lead to the incipient formation of the early foam cell lesion in atherogenesis and its localization. Particular emphasis will be placed on the intimal transport mechanisms that lead to the growth of extracellular lipid liposomes in the intima, since there is now substantial evidence that this growth is the triggering event in the complex sequence of processes that leads to the recruitment of blood borne monocytes into the sub-endothelial intima and their subsequent conversion to macrophages. The role of the endothelium, intimal proteoglycans and internal elastic lamina (IEL) in modulating the transport of low density lipoproteins (LDL) in the subendothelial space will be analyzed and a new hypothesis for the co-localization of liposome formation, cellular level endothelial leakage and monocyte entry described. The possible modifications of LDL in the lipsomes that facilitate the conversion of monocytes into foam cells is summarized. We also discuss the fluid dynamic aspects of intimal transport and the relationship of fluid shear stress to the localization of cellular level endothelial leakage of LDL. The effect of fluid shear on other endothelial cell functions has been recently reviewed in [1].

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RUTLEDGE, J., F. CURRY, P. DAVIS, and J. LENZ. "Paracellular mechanisms of low density lipoprotein (LDL) transport." Journal of Molecular and Cellular Cardiology 19 (1987): S7. http://dx.doi.org/10.1016/s0022-2828(87)80646-6.

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17

Olivecrona, G., M. Hultin, R. Savonen, O. Chevreuil, and T. Olivecrona. "Transport of LDL in plasma and lipoprotein metabolism." Atherosclerosis 109, no. 1-2 (September 1994): 86. http://dx.doi.org/10.1016/0021-9150(94)93360-x.

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18

Filipovic, N., M. Zivic, M. Obradovic, T. Djukic, Z. Markovic, and M. Rosic. "Numerical and experimental LDL transport through arterial wall." Microfluidics and Nanofluidics 16, no. 3 (July 28, 2013): 455–64. http://dx.doi.org/10.1007/s10404-013-1238-1.

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19

Cohn, W., M. A. Goss-Sampson, H. Grun, and D. P. R. Muller. "Plasma clearance and net uptake of α-tocopherol and low-density lipoprotein by tissues in WHHL and control rabbits." Biochemical Journal 287, no. 1 (October 1, 1992): 247–54. http://dx.doi.org/10.1042/bj2870247.

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The mechanism(s) of uptake of vitamin E (alpha-tocopherol) by tissues is poorly understood. It has, however, been suggested from studies in vitro that the apolipoprotein B/E (apo B/E) receptor pathway for low-density lipoprotein (LDL) may be involved. To investigate the role of the apo B/E receptor pathway in vivo, we have studied the transport and uptake of alpha-tocopherol by tissues in Watanabe Heritable Hyperlipidaemic (WHHL) rabbits, which lack functional LDL (apo B/E) receptors, and controls. [3H]alpha-Tocopherol incorporated within LDL labelled with [14C]sucrose was used in these studies, as this enabled the uptake of both alpha-tocopherol and LDL to be studied independently. The principal findings were as follows. (1) Concentrations of the circulating lipids (including alpha-tocopherol) and LDL were increased and the plasma fractional disappearance rates of alpha-tocopherol and LDL decreased in the WHHL rabbits. (2) The WHHL rabbits clear more LDL and alpha-tocopherol from the circulation than controls do, because of their increased pool sizes of alpha-tocopherol and LDL. (3) The lipoprotein composition of the WHHL rabbits differed from that of the controls, and there was exchange of alpha-tocopherol between the lipoprotein fractions in vivo and in vitro. (4) High-affinity apo B/E receptors were not essential for the uptake of alpha-tocopherol by tissues. (5) Evidence from the plasma-clearance and tissue data suggest that alpha-tocopherol can be taken up by tissues in association with, and also independent of, LDL. We conclude that there are several different mechanisms for the uptake of alpha-tocopherol by tissues, which include receptor-dependent and receptor-independent pathways, independent transport and co-transport of alpha-tocopherol and LDL, and uptake from a number of different lipoproteins.

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Vasandani, Chandna, Abdallah I. Kafrouni, Antonella Caronna, Yuriy Bashmakov, Michael Gotthardt, Jay D. Horton, and David K. Spady. "Upregulation of hepatic LDL transport by n-3 fatty acids in LDL receptor knockout mice." Journal of Lipid Research 43, no. 5 (May 2002): 772–84. http://dx.doi.org/10.1016/s0022-2275(20)30120-6.

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Soulis, J., G. Giannoglou, M. Dimitrakopoulou, V. Papaioannou, S. Logothetides, and D. Mikhailidis. "Influence of Oscillating Flow on LDL Transport and Wall Shear Stress in the Normal Aortic Arch." Open Cardiovascular Medicine Journal 3, no. 1 (September 17, 2009): 128–42. http://dx.doi.org/10.2174/1874192400903010128.

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Lipid accumulation in the aortic wall is an important factor in the development of atherosclerosis. The Low Density Lipoprotein (LDL) at the surface of the endothelium in relation to Wall Shear Stress (WSS) in the normal human aortic arch under unsteady, normal flow and mass conditions was computationally analysed. Concave sides of the aortic arch exhibit, relatively to the convex ones, elevated LDL levels at the surface of the endothelium for all time steps. At the peak systolic velocity, the LDL level reaches a value 23.0% higher than that at entrance in the ascending-descending aorta region. The corresponding LDL levels at the surface of the endothelium for the near minimum entrance velocity instant reaches 26.0%. During the cardiac cycle, the highest area averaged normalized LDL taken up as compared to the lowest one is 0.69%. WSS plays an important role in the lipid accumulation. Low WSS regions are exposed to high LDL levels at the surface of the endothelium. Regions of elevated LDL levels do not necessarily co-locate to the sites of lowest WSS. The near wall paths of the velocities might be the most important factor for the elevated LDL levels at the surface of the endothelium.

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Goldberg, Doron, and Soliman Khatib. "Atherogenesis, Transcytosis, and the Transmural Cholesterol Flux: A Critical Review." Oxidative Medicine and Cellular Longevity 2022 (April 14, 2022): 1–14. http://dx.doi.org/10.1155/2022/2253478.

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The recently described phenomenon of cholesterol-loaded low-density lipoproteins (LDL) entering the arterial wall from the lumen by transcytosis has been accepted as an alternative for the long-held concept that atherogenesis involves only passive LDL movement across an injured or dysfunctional endothelial barrier. This active transport of LDL can now adequately explain why plaques (atheromas) appear under an intact, uninjured endothelium. However, the LDL transcytosis hypothesis is still questionable, mainly because the process serves no clear physiological purpose. Moreover, central components of the putative LDL transcytosis apparatus are shared by the counter process of cholesterol efflux and reverse cholesterol transport (RCT) and therefore can essentially create an energy-wasting futile cycle and paradoxically be pro- and antiatherogenic simultaneously. Hence, by critically reviewing the literature, we wish to put forward an alternative interpretation that, in our opinion, better fits the experimental evidence. We assert that most of the accumulating cholesterol (mainly as LDL) reaches the intima not from the lumen by transcytosis, but from the artery’s inner layers: the adventitia and media. We have named this directional cholesterol transport transmural cholesterol flux (TCF). We suggest that excess cholesterol, diffusing from the avascular (i.e., devoid of blood and lymph vessels) media’s smooth muscle cells, is cleared by the endothelium through its apical membrane. A plaque is formed when this cholesterol clearance rate lags behind its rate of arrival by TCF.

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Dehouck, Bénédicte, Laurence Fenart, Marie-Pierre Dehouck, Annick Pierce, Gérard Torpier, and Roméo Cecchelli. "A New Function for the LDL Receptor: Transcytosis of LDL across the Blood–Brain Barrier." Journal of Cell Biology 138, no. 4 (August 25, 1997): 877–89. http://dx.doi.org/10.1083/jcb.138.4.877.

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Lipoprotein transport across the blood–brain barrier (BBB) is of critical importance for the delivery of essential lipids to the brain cells. The occurrence of a low density lipoprotein (LDL) receptor on the BBB has recently been demonstrated. To examine further the function of this receptor, we have shown using an in vitro model of the BBB, that in contrast to acetylated LDL, which does not cross the BBB, LDL is specifically transcytosed across the monolayer. The C7 monoclonal antibody, known to interact with the LDL receptor-binding domain, totally blocked the transcytosis of LDL, suggesting that the transcytosis is mediated by the receptor. Furthermore, we have shown that cholesterol-depleted astrocytes upregulate the expression of the LDL receptor at the BBB. Under these conditions, we observed that the LDL transcytosis parallels the increase in the LDL receptor, indicating once more that the LDL is transcytosed by a receptor-mediated mechanism. The nondegradation of the LDL during the transcytosis indicates that the transcytotic pathway in brain capillary endothelial cells is different from the LDL receptor classical pathway. The switch between a recycling receptor to a transcytotic receptor cannot be explained by a modification of the internalization signals of the cytoplasmic domain of the receptor, since we have shown that LDL receptor messengers in growing brain capillary ECs (recycling LDL receptor) or differentiated cells (transcytotic receptor) are 100% identical, but we cannot exclude posttranslational modifications of the cytoplasmic domain, as demonstrated for the polymeric immunoglobulin receptor. Preliminary studies suggest that caveolae are likely to be involved in the potential transport of LDL from the blood to the brain.

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Sakellarios, Antonis I., Paschalis Bizopoulos, Michail I. Papafaklis, Lambros Athanasiou, Themis Exarchos, Christos V. Bourantas, Katerina K. Naka, et al. "Natural History of Carotid Atherosclerosis in Relation to the Hemodynamic Environment." Angiology 68, no. 2 (September 29, 2016): 109–18. http://dx.doi.org/10.1177/0003319716644138.

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Carotid atherosclerosis may lead to devastating clinical outcomes such as stroke. Data on the value of local factors in predicting progression in carotid atherosclerosis are limited. Our aim was to investigate the association of local endothelial shear stress (ESS) and low-density lipoprotein (LDL) accumulation with the natural history of atherosclerotic disease using a series of 3 time points of human magnetic resonance data. Three-dimensional lumen/wall reconstruction was performed in 12 carotids, and blood flow and LDL mass transport modeling were performed. Our results showed that an increase in plaque thickness and a decrease in lumen size were associated with low ESS and high LDL accumulation in the arterial wall. Low ESS (odds ratio [OR]: 2.99; 95% confidence interval [CI]: 2.31-3.88; P < .001 vs higher ESS) and high LDL concentration (OR: 3.26; 95% CI: 2.44-4.36; P < .001 vs higher LDL concentration) were significantly associated with substantial local plaque growth. Low ESS and high LDL accumulation both presented a diagnostic accuracy of 67% for predicting plaque growth regions. Modeling of blood flow and LDL mass transport show promise in predicting progression of carotid atherosclerosis.

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Ding, Zufeng, Yubo Fan, Xiaoyan Deng, Fan Zhan, and Hongyan Kang. "Effect of swirling flow on the uptakes of native and oxidized LDLs in a straight segment of the rabbit thoracic aorta." Experimental Biology and Medicine 235, no. 4 (April 2010): 506–13. http://dx.doi.org/10.1258/ebm.2009.009245.

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To elucidate the physiological significance of the spiral flow in the arterial system from the viewpoint of atherogenic lipid transport, an ex vivo experimental comparative study was designed to investigate the effect of swirling flow on the distribution of native 3,3′-dioctadecylindocarbocyanine-low-density lipoprotiens (DiI-LDL) and DiI-ox-LDL uptakes by segments of the rabbit thoracic aorta. The experimental results showed that when compared with the normal flow, the swirling flow generated in the test arteries significantly reduced the DiI-LDL and DiI-ox-LDL uptakes by the arterial walls. The results also showed that the values of DiI-ox-LDL uptake were higher than those of DiI-LDL uptake at the same sample position in both the normal flow group and the swirling flow group. Most interestingly, the experimental results found that the percentage increase in DiI-ox-LDL uptake was much larger than that in DiI-LDL uptake when the perfusion duration increased from 3 to 24 h. In conclusion, the present study substantiated the hypothesis that the spiral flow in the arterial system plays a beneficial role in protecting the arterial wall from atherogenesis. Meanwhile, it supported the concept that the receptor-mediated bindings of LDL uptake, the barrier function of the arterial endothelial linings and the mass transport phenomenon of LDL concentration polarization are all involved in the infiltration/accumulation of atherogenic lipids within the arterial wall.

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Straley, Kimberly S., and Samuel A. Green. "Rapid Transport of Internalized P-Selectin to Late Endosomes and the Tgn." Journal of Cell Biology 151, no. 1 (October 2, 2000): 107–16. http://dx.doi.org/10.1083/jcb.151.1.107.

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Prior studies on receptor recycling through late endosomes and the TGN have suggested that such traffic may be largely limited to specialized proteins that reside in these organelles. We present evidence that efficient recycling along this pathway is functionally important for nonresident proteins. P-selectin, a transmembrane cell adhesion protein involved in inflammation, is sorted from recycling cell surface receptors (e.g., low density lipoprotein [LDL] receptor) in endosomes, and is transported from the cell surface to the TGN with a half-time of 20–25 min, six to seven times faster than LDL receptor. Native P-selectin colocalizes with LDL, which is efficiently transported to lysosomes, for 20 min after internalization, but a deletion mutant deficient in endosomal sorting activity rapidly separates from the LDL pathway. Thus, P-selectin is sorted from LDL receptor in early endosomes, driving P-selectin rapidly into late endosomes. P-selectin then recycles to the TGN as efficiently as other receptors. Thus, the primary effect of early endosomal sorting of P-selectin is its rapid delivery to the TGN, with rapid turnover in lysosomes a secondary effect of frequent passage through late endosomes. This endosomal sorting event provides a mechanism for efficiently recycling secretory granule membrane proteins and, more generally, for downregulating cell surface receptors.

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Liu, Biyue, and Dalin Tang. "Mass Transport of LDL in Stenotic Right Coronary Arteries." Molecular & Cellular Biomechanics 16, S2 (2019): 25–26. http://dx.doi.org/10.32604/mcb.2019.06825.

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Cancel, L. M., A. Fitting, and J. M. Tarbell. "In vitro study of LDL transport under convective conditions." Journal of Biomechanics 39 (January 2006): S376. http://dx.doi.org/10.1016/s0021-9290(06)84516-1.

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Cancel, Limary M., and John M. Tarbell. "The role of mitosis in LDL transport through cultured endothelial cell monolayers." American Journal of Physiology-Heart and Circulatory Physiology 300, no. 3 (March 2011): H769—H776. http://dx.doi.org/10.1152/ajpheart.00445.2010.

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We ( 7 ) have previously shown that leaky junctions associated with dying or dividing cells are the dominant pathway for LDL transport under convective conditions, accounting for >90% of the transport. We ( 8 ) have also recently shown that the permeability of bovine aortic endothelial cell monolayers is highly correlated with their rate of apoptosis and that inhibiting apoptosis lowers the permeability of the monolayers to LDL. To explore the role of mitosis in the leaky junction pathway, the microtubule-stabilizing agent paclitaxel was used to alter the rate of mitosis, and LDL flux and water flux ( Jv) were measured. Control monolayers had an average mitosis rate of 0.029%. Treatment with paclitaxel (2.5 μM) for 1.5, 3, 4.5, or 6 h yielded increasing rates of mitosis ranging from 0.099% to 1.03%. The convective permeability of LDL (Pe) increased up to fivefold, whereas Jv increased up to threefold, over this range of mitosis rates. We found strong correlations between the mitosis rate and both Pe and Jv. However, compared with our previous apoptosis study ( 8 ), we found that mitosis was only half as effective as apoptosis in increasing Pe. The results led us to conclude that while mitotsis-related leaky junctions might play a role in the initial infiltration of LDL into the artery wall, the progression of atherosclerosis might be more closely correlated with apoptosis-related leaky junctions.

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Flessner, M. F., R. Mejia, and M. A. Knepper. "Ammonium and bicarbonate transport in isolated perfused rodent long-loop thin descending limbs." American Journal of Physiology-Renal Physiology 264, no. 3 (March 1, 1993): F388—F396. http://dx.doi.org/10.1152/ajprenal.1993.264.3.f388.

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Ammonium accumulates in the renal medullas of antidiuretic mammals. The accumulation process is thought to involve countercurrent multiplication, energy-dependent recycling between the ascending and descending limbs of Henle's loop. To investigate the role of the long-loop thin descending limb (LDL) in countercurrent multiplication of ammonium, we have perfused outer medullary and inner medullary subsegments of the chinchilla LDL (and inner medullary subsegments of rat LDL) in vitro and measured the fluxes of total ammonia and total CO2. No spontaneous fluxes of total ammonia or total CO2 occurred in the absence of imposed concentration gradients. When transepithelial concentration gradients were imposed, passive total ammonia and total CO2 transport were observed in all subsegments, although the permeabilities varied with distance along the descending limb. Passive total ammonia transport occurred through a combination of NH3 and direct NH4+ permeation. The outer medullary segment was the most permeable to NH4+. The deep inner medullary segment was the most permeable to bicarbonate. Addition of carbonic anhydrase to the lumen accelerated passive NH3 entry in the outer medullary LDL, indicating that little or no luminal carbonic anhydrase is endogenously present. The passive secretion of NH4+ and NH3 into the LDL may contribute to the countercurrent multiplication of ammonium in the rodent renal medulla.

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31

Koshiba, Nobuko, Joji Ando, Xian Chen, and Toshiaki Hisada. "Multiphysics Simulation of Blood Flow and LDL Transport in a Porohyperelastic Arterial Wall Model." Journal of Biomechanical Engineering 129, no. 3 (November 11, 2006): 374–85. http://dx.doi.org/10.1115/1.2720914.

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Atherosclerosis localizes at a bend and∕or bifurcation of an artery, and low density lipoproteins (LDL) accumulate in the intima. Hemodynamic factors are known to affect this localization and LDL accumulation, but the details of the process remain unknown. It is thought that the LDL concentration will be affected by the filtration flow, and that the velocity of this flow will be affected by deformation of the arterial wall. Thus, a coupled model of a blood flow and a deformable arterial wall with filtration flow would be invaluable for simulation of the flow field and concentration field in sequence. However, this type of highly coupled interaction analysis has not yet been attempted. Therefore, we performed a coupled analysis of an artery with multiple bends in sequence. First, based on the theory of porous media, we modeled a deformable arterial wall using a porohyperelastic model (PHEM) that was able to express both the filtration flow and the viscoelastic behavior of the living tissue, and simulated a blood flow field in the arterial lumen, a filtration flow field and a displacement field in the arterial wall using a fluid-structure interaction (FSI) program code by the finite element method (FEM). Next, based on the obtained results, we further simulated LDL transport using a mass transfer analysis code by the FEM. We analyzed the PHEM in comparison with a rigid model. For the blood flow, stagnation was observed downward of the bends. The direction of the filtration flow was only from the lumen to the wall for the rigid model, while filtration flows from both the wall to the lumen and the lumen to the wall were observed for the PHEM. The LDL concentration was high at the lumen∕wall interface for both the PHEM and rigid model, and reached its maximum value at the stagnation area. For the PHEM, the maximum LDL concentration in the wall in the radial direction was observed at the position of 3% wall thickness from the lumen∕wall interface, while for the rigid model, it was observed just at the lumen∕wall interface. In addition, the peak LDL accumulation area of the PHEM moved about according to the pulsatile flow. These results demonstrate that the blood flow, arterial wall deformation, and filtration flow all affect the LDL concentration, and that LDL accumulation is due to stagnation and the presence of filtration flow. Thus, FSI analysis is indispensable.

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Khaitan, Alka, Gunther Fless, and Jane Hoover-Plow. "Phospholipase A2 Modification Enhances Lipoprotein(a) Binding to the Subendothelial Matrix." Thrombosis and Haemostasis 79, no. 03 (1998): 640–48. http://dx.doi.org/10.1055/s-0037-1614960.

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SummaryLipoprotein(a), Lp(a), is found in the extracellular matrix in athero-sclerotic plaques, but with a different localization than LDL. A two-compartment system, with a monolayer of endothelial cells forming a barrier, was used to compare the transport, cell binding, and retention of Lp(a) and LDL into the subendothelial matrix. Baseline values for transport and retention of Lp(a) and LDL were not significantly different. Incubation with lipoprotein lipase or sphingomyelinase caused modest and similar increases in transport and retention of the two lipo-proteins. In contrast, incubation with phospholipase A2 (PLA2) resulted in a marked (4-fold) increase in retention of Lp(a) on the subendothelial matrix, but a lesser (2-fold) increase in LDL retention. Moreover, PLA2 treatment of Lp(a) enhanced its binding to individual matrix proteins (fibronectin, laminin, or collagen) by 4-10 times above that of LDL. The enzymatic activity of PLA2 was responsible for its effect on Lp(a) binding. The lysine binding sites of Lp(a) contributed to the increased binding of PLA2-modified Lp(a) to the matrix, and the enhanced lysine binding functions of PLA2-modified Lp(a) was demonstrated by two independent approaches. Thus, PLA2 modification leads to enhanced interactions of lipoproteins with the extracellular matrix, and this effect is more pronounced with Lp(a).

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Mejia, R., M. F. Flessner, and M. A. Knepper. "Model of ammonium and bicarbonate transport along LDL: implications for alkalinization of luminal fluid." American Journal of Physiology-Renal Physiology 264, no. 3 (March 1, 1993): F397—F403. http://dx.doi.org/10.1152/ajprenal.1993.264.3.f397.

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Luminal fluid exiting the proximal convoluted tubule of a juxtamedullary nephron is alkalinized as it passes through the long-loop thin descending limb of Henle (LDL). Three potential mechanisms of alkalinization are: 1) concentration of bicarbonate by water abstraction, 2) direct bicarbonate entry, and 3) NH3 entry. We have used a mathematical model of the LDL to investigate these mechanisms. With permeabilities of HCO3-, NH3, and NH4+ measured for subsegments of the chinchilla LDL [M. F. Flessner, R. Mejia, and M. A. Knepper. Am. J. Physiol. 264 (Renal Fluid Electrolyte Physiol. 33):F388-F396, 1993], the osmotic water permeability of each segment [C.-L. Chou and M. A. Knepper. Am. J. Physiol. 263 (Renal Fluid Electrolyte Physiol. 32):F417-F426, 1992], and appropriate parameters from the literature, we have used the model to calculate hypothetical pH, HCO3- concentration, and NH3 concentration of the luminal fluid as it descends the LDL within an assumed interstitium. After eliminating each mechanism in turn by setting the appropriate permeability to zero, we recalculated the axial profiles. Our results suggest that, although all three mechanisms individually contribute to LDL alkalinization, NH3 entry likely plays the dominant role.

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34

Zeng, Zhongqing, Yongyi Yin, Kung-Ming Jan, and David S. Rumschitzki. "Macromolecular transport in heart valves. II. Theoretical models." American Journal of Physiology-Heart and Circulatory Physiology 292, no. 6 (June 2007): H2671—H2686. http://dx.doi.org/10.1152/ajpheart.00608.2006.

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This paper proposes a new, two-dimensional convection-diffusion model for macromolecular transport in heart valves based on horseradish peroxidase (HRP) experiments on rats presented in the first of the papers in this series (Part I; Zeng Z, Yin Y, Huang AL, Jan KM, Rumschitzki DS. Am J Physiol Heart Circ Physiol 292: H2664–H2670, 2007). Experiments require two valvular intimae, one underneath each endothelium. Tompkins et al. (Tompkins RG, Schnitzer JJ, Yarmush ML. Circ Res 64: 1213–1223, 1989) found large variations in shape and magnitude in transvalvular 125I-labeled low-density lipoprotein (LDL) profiles from identical experiments on four squirrel monkeys. Their one-dimensional, uniform-medium diffusion-only model fit three parameters independently for each profile; data variability resulted in large parameter spreads. Our theory aims to explain their data with one parameter set. It uses measured parameters and some aortic values but fits the endothelial mass transfer coefficient ( ka = kv = 1.63 × 10−8 cm/s, where subscripts a and v indicate aortic aspect and ventricular aspect, respectively) and middle layer permeability ( K[Formula: see text]= 2.28 × 10−16 cm2) and LDL diffusion coefficient [ D2(LDL) = 5.93 × 10−9 cm2/s], using one of Tompkins et al.'s profiles, and fixes them throughout. It accurately predicts Part I's rapid localized HRP leakage spot growth rate in rat leaflets that results from the intima's much sparser structure, dictating its far larger transport parameters [ K[Formula: see text]= 1.10 × 10−12 cm2, D1(LDL/HRP) = 1.02/4.09 × 10−7 cm2/s] than the middle layer. This contrasts with large arteries with similarly large HRP spots, since the valve has no internal elastic lamina. The model quantitatively explains all of Tompkins et al.'s monkey profiles with these same parameters. Different numbers and locations of isolated macromolecular leaks on both aspects and different section-leak(s) distances yield all profiles.

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Dashty, Monireh, Mohammad Motazacker, Johannes Levels, Marcel de Vries, Morteza Mahmoudi, Maikel Peppelenbosch, and Farhad Rezaee. "Proteome of human plasma very low-density lipoprotein and low-density lipoprotein exhibits a link with coagulation and lipid metabolism." Thrombosis and Haemostasis 111, no. 03 (2014): 518–30. http://dx.doi.org/10.1160/th13-02-0178.

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SummaryApart from transporting lipids through the body, the human plasma lipoproteins very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) are also thought to serve as a modality for intra-organismal protein transfer, shipping proteins with important roles in inflammation and thrombosis from the site of synthesis to effector locations. To better understand the role of VLDL and LDL in the transport of proteins, we applied a combination of LTQ ORBITRAP-XL (nLC-MS/MS) with both in-SDS-PAGE gel and in-solution tryptic digestion of pure and defined VLDL and LDL fractions. We identified the presence of 95 VLDL-and 51 LDL-associated proteins including all known apolipoproteins and lipid transport proteins, and intriguingly a set of coagulation proteins, complement system and anti-microbial proteins. Prothrombin, protein S, fibrinogen γ, PLTP, CETP, CD14 and LBP were present on VLDL but not on LDL. Prenylcysteine oxidase 1, dermcidin, cathelicidin antimicrobial peptide, TFPI-1 and fibrinogen α chain were associated with both VLDL and LDL. Apo A-V is only present on VLDL and not on LDL. Collectively, this study provides a wealth of knowledge on the protein constituents of the human plasma lipoprotein system and strongly supports the notion that protein shuttling through this system is involved in the regulation of biological processes. Human diseases related to proteins carried by VLDL and LDL can be divided in three major categories: 1 – dyslipidaemia, 2 – atherosclerosis and vascular disease, and 3 – coagulation disorders.

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Kallol, Sampada, and Christiane Albrecht. "Materno-fetal cholesterol transport during pregnancy." Biochemical Society Transactions 48, no. 3 (May 5, 2020): 775–86. http://dx.doi.org/10.1042/bst20190129.

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Cholesterol is a major nutrient required for fetal growth. It is also a precursor for the synthesis of steroid hormones and essential for the development and maturation of fetal organs. During pregnancy, the placenta controls the transport of cholesterol from the mother to the fetus and vice versa. Cholesterol originating from the maternal circulation has to cross two main membrane barriers to reach the fetal circulation: Firstly, cholesterol is acquired by the apical side of the syncytiotrophoblast (STB) from the maternal circulation as high-density lipoprotein (HDL)-, low-density lipoprotein (LDL)- or very-low-density lipoprotein (VLDL)-cholesterol and secreted at the basal side facing the villous stroma. Secondly, from the villous stroma cholesterol is taken up by the endothelium of the fetal vasculature and transported to the fetal vessels. The proteins involved in the uptake of HDL-, LDL-, VLDL- or unesterified-cholesterol are scavenger receptor type B class 1 (SR-B1), cubulin, megalin, LDL receptor (LDLR) or Niemann–Pick-C1 (NPC1) which are localized at the apical and/or basal side of the STB or at the fetal endothelium. Through interaction with apolipoproteins (e.g. apoA1) cholesterol is effluxed either to the maternal or fetal circulation via the ATP-binding-cassette (ABC)-transporter A1 and ABCG1 localized at the apical/basal side of the STB or the endothelium. In this mini-review, we summarize the transport mechanisms of cholesterol across the human placenta, the expression and localization of proteins involved in the uptake and efflux of cholesterol, and the expression pattern of cholesterol transport proteins in pregnancy pathologies such as pre-eclampsia, gestational diabetes mellitus and intrauterine growth retardation.

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Tompkins, R. G., M. L. Yarmush, J. J. Schnitzer, C. K. Colton, K. A. Smith, and M. B. Stemerman. "Low-density lipoprotein transport in blood vessel walls of squirrel monkeys." American Journal of Physiology-Heart and Circulatory Physiology 257, no. 2 (August 1, 1989): H452—H464. http://dx.doi.org/10.1152/ajpheart.1989.257.2.h452.

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Transmural accumulations of low-density lipoprotein (LDL) were examined in the blood vessel walls of four squirrel monkeys. Vascular wall concentrations of LDL were measured using quantitative autoradiography after 125I-labeled LDL circulation for 30 min. Profiles of relative tissue concentration from different sections in the same region were similar to each other, and there was little animal-to-animal variation. Concentrations were highest near the luminal endothelium, lower near the medial-adventitial border, and lowest within the media. Profiles from different regions fell into three groups: 1) aortic samples had steep intimal concentration gradients and near-zero media concentrations; 2) the iliac, femoral, popliteal, and common carotid arteries had higher intimal concentrations than group 1 but had similar concentrations deep within the media; and 3) the cerebral and coronary arteries, inferior vena cava, and pulmonary artery had intimal concentrations that were similar to group 2, but the concentrations deep within the media were greater than either groups 1 or 2. Arterial bifurcation profiles from the inner wall and the outer walls were similar to each other and to profiles from the upstream and downstream areas. Out of 280 total sites examined, 15 examples of profiles with substantially increased concentrations near the luminal endothelium were found scattered throughout the cardiovascular system, demonstrating that there are focal regions throughout the cardiovascular system which have greatly increased 125I-LDL transendothelial permeability.

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Tamim, Hossein, Abbas Abbassi, and Nasser Fatouraee. "On the effects of straight extremities on low-density lipoprotein transport in the concentration boundary layer of curved arteries." International Journal of Numerical Methods for Heat & Fluid Flow 30, no. 7 (November 18, 2019): 3701–19. http://dx.doi.org/10.1108/hff-07-2019-0564.

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Purpose The purpose of this paper is to analyze the influence of curvature on the transport of low-density lipoprotein (LDL) through a curved artery and concentration boundary layer characteristics numerically. Design/methodology/approach By using a projection method based on the second-order central difference discretization, the authors solve the set of governing equations, which consists of Navier–Stokes, continuity and species transport. The effects of initial straight length, as well as the curvature and wall shear stress (WSS) on LDL transport in a curved artery are established in this paper. Findings The obtained numerical results imply that the LDL concentration boundary layer thickness decreases in the outer part of the curved artery and increases in the inner part for both with or without initial straight length. The effect of Reynolds number on the concentration distribution in a curved artery with initial straight length is more pronounced than that on a fully curved artery, although an opposite trend was seen for the curvature ratio. The maximum surface LDL concentration is related to the regions with minimum WSS in the inner part of the curved artery, which has more potential the formation of atherosclerosis. Originality/value The authors present a comprehensive concentration distribution of LDL in the concentration boundary layer of the curved artery. The authors also characterize and predict the influence of curvature on the formation and development of atherosclerosis within the arterial wall.

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Olgac, Ufuk, Vartan Kurtcuoglu, and Dimos Poulikakos. "Computational modeling of coupled blood-wall mass transport of LDL: effects of local wall shear stress." American Journal of Physiology-Heart and Circulatory Physiology 294, no. 2 (February 2008): H909—H919. http://dx.doi.org/10.1152/ajpheart.01082.2007.

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The work herein represents a novel approach for the modeling of low-density lipoprotein (LDL) transport from the artery lumen into the arterial wall, taking into account the effects of local wall shear stress (WSS) on the endothelial cell layer and its pathways of volume and solute flux. We have simulated LDL transport in an axisymmetric representation of a stenosed coronary artery, where the endothelium is represented by a three-pore model that takes into account the contributions of the vesicular pathway, normal junctions, and leaky junctions also employing the local WSS to yield the overall volume and solute flux. The fraction of leaky junctions is calculated as a function of the local WSS based on published experimental data and is used in conjunction with the pore theory to determine the transport properties of this pathway. We have found elevated levels of solute flux at low shear stress regions because of the presence of a larger number of leaky junctions compared with high shear stress regions. Accordingly, we were able to observe high LDL concentrations in the arterial wall in these low shear stress regions despite increased filtration velocity, indicating that the increase in filtration velocity is not sufficient for the convective removal of LDL.

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Wang, Ming-Dong, Robert S. Kiss, Vivian Franklin, Heidi M. McBride, Stewart C. Whitman, and Yves L. Marcel. "Different cellular traffic of LDL-cholesterol and acetylated LDL-cholesterol leads to distinct reverse cholesterol transport pathways." Journal of Lipid Research 48, no. 3 (December 5, 2006): 633–45. http://dx.doi.org/10.1194/jlr.m600470-jlr200.

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Deyranlou, Amin, Hamid Niazmand, Mahmood-Reza Sadeghi, and Yaser Mesri. "Non-Newtonian effects of blood on LDL transport inside the arterial lumen and across multi-layered arterial wall with and without stenosis." International Journal of Modern Physics C 27, no. 01 (January 2016): 1650003. http://dx.doi.org/10.1142/s0129183116500030.

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Blood non-Newtonian behavior on low-density lipoproteins (LDL) accumulation is analyzed numerically, while fluid-multilayered arteries are adopted for nonstenotic and 30%–60% symmetrical stenosed models. Present model considers non-Newtonian effects inside the lumen and within arterial layers simultaneously, which has not been examined in previous studies. Navier–Stokes equations are solved along with the mass transport convection–diffusion equations and Darcy’s model for species transport inside the luminal flow and across wall layers, respectively. Carreau model for the luminal flow and the modified Darcy equation for the power-law fluid within arterial layers are employed to model blood rheological characteristics, appropriately. Results indicate that in large arteries with relatively high Reynolds number Newtonian model estimates LDL concentration patterns well enough, however, this model seriously incompetent for regions with low WSS. Moreover, Newtonian model for plasma underestimates LDL concentration especially on luminal surface and across arterial wall. Therefore, applying non-Newtonian model seems essential for reaching to a more accurate estimation of LDL distribution in the artery. Finally, blood flow inside constricted arteries demonstrates that LDL concentration patterns along the stenoses inside the luminal flow and across arterial layers are strongly influenced as compared to the nonstenotic arteries. Additionally, among four stenosis severity grades, 40% stenosis is prone to more LDL accumulation along the post-stenotic regions.

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Stangeby, D. Kim, and C. Ross Ethier. "Coupled Computational Analysis of Arterial LDL Transport -- Effects of Hypertension." Computer Methods in Biomechanics and Biomedical Engineering 5, no. 3 (January 2002): 233–41. http://dx.doi.org/10.1080/10255840290010733.

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43

Hansen, C., D. Bay, M. R. Jensen, B. Gervang, H. M. Jensen, S. A. Thrysøe, and J. V. Nygaard. "Numerical simulation of LDL transport through the carotid arterial wall." Computer Methods in Biomechanics and Biomedical Engineering 17, sup1 (July 30, 2014): 20–21. http://dx.doi.org/10.1080/10255842.2014.931074.

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Tada, Shigeru, and Hirokazu Ozono. "Computational study of LDL mass transport in the artery wall." Journal of Biorheology 25, no. 1-2 (May 17, 2011): 27–35. http://dx.doi.org/10.1007/s12573-011-0034-3.

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45

Trinh, Michael N., Michael S. Brown, Joseph L. Goldstein, Jaeil Han, Gonçalo Vale, Jeffrey G. McDonald, Joachim Seemann, Joshua T. Mendell, and Feiran Lu. "Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine." Proceedings of the National Academy of Sciences 117, no. 31 (July 20, 2020): 18521–29. http://dx.doi.org/10.1073/pnas.2010682117.

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Animal cells acquire cholesterol from receptor-mediated uptake of low-density lipoprotein (LDL), which releases cholesterol in lysosomes. The cholesterol moves to the endoplasmic reticulum (ER), where it inhibits production of LDL receptors, completing a feedback loop. Here we performed a CRISPR-Cas9 screen in human SV589 cells for genes required for LDL-derived cholesterol to reach the ER. We identified the gene encoding PTDSS1, an enzyme that synthesizes phosphatidylserine (PS), a phospholipid constituent of the inner layer of the plasma membrane (PM). In PTDSS1-deficient cells where PS is low, LDL cholesterol leaves lysosomes but fails to reach the ER, instead accumulating in the PM. The addition of PS restores cholesterol transport to the ER. We conclude that LDL cholesterol normally moves from lysosomes to the PM. When the PM cholesterol exceeds a threshold, excess cholesterol moves to the ER in a process requiring PS. In the ER, excess cholesterol acts to reduce cholesterol uptake, preventing toxic cholesterol accumulation. These studies reveal that one lipid—PS—controls the movement of another lipid—cholesterol—between cell membranes. We relate these findings to recent evidence indicating that PM-to-ER cholesterol transport is mediated by GRAMD1/Aster proteins that bind PS and cholesterol.

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Kao, C. H., V. C. Yang, J. K. Chen, and J. S. Kuo. "Transport pathways of low-density lipoproteins by arterial endothelium of hypercholesterolemic rats." Proceedings, annual meeting, Electron Microscopy Society of America 51 (August 1, 1993): 314–15. http://dx.doi.org/10.1017/s0424820100147417.

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Atherosclerosis is more likely to occur at the branched regions of the large or mediumsized arteries. Physiological evidences show that changes in endothelial permeability at the branched regions can cause low density lipoproteins (LDL) to filtrate and accumulate in the intima. However, the LDL transport pathways across the arterial endothelium at the ultrastructural level still remain uncertain. The purpose of this experiment is utilizing fluorescein 1,1' -dioctadecyl-3,3,3',3' -tetramethylindocarbocyanine perchlorate (Dil) and colloidal gold as the tracer substances to investigate the transport pathways of LDL in the branched and the unbranched regions of arteries in the diet-induced hypereholesterolemic rats.Rat or human LDL was coupled to Dil or to 10-15nm colloidal gold particles according to the standard procedures. Male Srague-Dawley rats, weighing approximately 250 gm were fed high-cholesterol diets over a period of 12 months. At 6 and 12 months after feeding, animals were anesthetized by intraperitoneal injections of sodium pentobarbitol. The vascular bed was cleared of blood by perfusion with oxygenated PBS supplemented with 0.25% glucose and 1 mM CaCl2 at 37°C through the left ventricle. After the blood washed out, the right and the left femoral arteries and the left ventricle, the thoracic and the abdominal aorta were cannulated with polyethylene tubings. The tubings between the left ventricle and the thoracic aorta and the tubings between the abdominal aorta and the femoral arteries were connected with peristaltic pump to form two closed circuits.

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Lewandowska, Hanna, and Monika Kalinowska. "New Polyphenol-Containing LDL Nano-Preparations in Oxidative Stress and DNA Damage: A Potential Route for Cell-Targeted PP Delivery." Materials 13, no. 22 (November 12, 2020): 5106. http://dx.doi.org/10.3390/ma13225106.

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Low-density lipoprotein (LDL) preparations of the chosen polyphenols (PPs) were prepared for the first time in the literature. The solubility of the PPs in the lipidic core of the LDL increased with the increase of their lipophilicity. The anti-/pro-oxidative properties and toxicity of LDL-entrapped PPs toward A 2780 human ovarian cancer cells were examined. The obtained preparations were found to be stable in PBS, and characterized by low toxicity. A binding affinity study revealed that the uptake of PP-loaded LDL particles is non-receptor-specific under experimental conditions. The antioxidative potential of the obtained PPs-doped LDL preparations was shown to be higher than for the PPs themselves, probably due to facilitating transport of LDL preparations into the cellular milieu, where they can interact with the cellular systems and change the redox status of the cell. The PPs-loaded LDL displayed the highest protective effect against Fenton-type reaction induced oxidative DNA damage.

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Cedó, Lídia, Jari Metso, David Santos, Annabel García-León, Núria Plana, Sonia Sabate-Soler, Noemí Rotllan, et al. "LDL Receptor Regulates the Reverse Transport of Macrophage-Derived Unesterified Cholesterol via Concerted Action of the HDL-LDL Axis." Circulation Research 127, no. 6 (August 28, 2020): 778–92. http://dx.doi.org/10.1161/circresaha.119.316424.

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Rationale: The HDL (high-density lipoprotein)-mediated stimulation of cellular cholesterol efflux initiates macrophage-specific reverse cholesterol transport (m-RCT), which ends in the fecal excretion of macrophage-derived unesterified cholesterol (UC). Early studies established that LDL (low-density lipoprotein) particles could act as efficient intermediate acceptors of cellular-derived UC, thereby preventing the saturation of HDL particles and facilitating their cholesterol efflux capacity. However, the capacity of LDL to act as a plasma cholesterol reservoir and its potential impact in supporting the m-RCT pathway in vivo both remain unknown. Objective: We investigated LDL contributions to the m-RCT pathway in hypercholesterolemic mice. Methods and Results: Macrophage cholesterol efflux induced in vitro by LDL added to the culture media either alone or together with HDL or ex vivo by plasma derived from subjects with familial hypercholesterolemia was assessed. In vivo, m-RCT was evaluated in mouse models of hypercholesterolemia that were naturally deficient in CETP (cholesteryl ester transfer protein) and fed a Western-type diet. LDL induced the efflux of radiolabeled UC from cultured macrophages, and, in the simultaneous presence of HDL, a rapid transfer of the radiolabeled UC from HDL to LDL occurred. However, LDL did not exert a synergistic effect on HDL cholesterol efflux capacity in the familial hypercholesterolemia plasma. The m-RCT rates of the LDLr (LDL receptor)-KO (knockout), LDLr-KO/APOB100, and PCSK9 (proprotein convertase subtilisin/kexin type 9)-overexpressing mice were all significantly reduced relative to the wild-type mice. In contrast, m-RCT remained unchanged in HAPOB100 Tg (human APOB100 transgenic) mice with fully functional LDLr, despite increased levels of plasma APO (apolipoprotein)-B–containing lipoproteins. Conclusions: Hepatic LDLr plays a critical role in the flow of macrophage-derived UC to feces, while the plasma increase of APOB-containing lipoproteins is unable to stimulate m-RCT. The results indicate that, besides the major HDL-dependent m-RCT pathway via SR-BI (scavenger receptor class B type 1) to the liver, a CETP-independent m-RCT path exists, in which LDL mediates the transfer of cholesterol from macrophages to feces. Graphical Abstract: A graphical abstract is available for this article.

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49

Zager, Richard A., Ali C. M. Johnson, and Sherry Y. Hanson. "Proximal tubular cholesterol loading after mitochondrial, but not glycolytic, blockade." American Journal of Physiology-Renal Physiology 285, no. 6 (December 2003): F1092—F1099. http://dx.doi.org/10.1152/ajprenal.00187.2003.

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Diverse forms of injury cause proximal tubular cholesterol accumulation. However, underlying mechanisms in general, and those involved with ATP depletion injury in particular, remain poorly defined. To help elucidate this issue, cholesterol homeostasis and its determinants were assessed after partial ATP depletion states. Serum-exposed HK-2 cells were subjected to mild ATP depletion, induced by mitochondrial inhibition (antimycin A; AA) or glycolytic blockade (2-deoxyglucose; DG). Four or 18 h later, cell cholesterol levels, hydroxymethylglutaryl (HMG)-CoA reductase (HMGCR), the LDL receptor (LDL-R), and ABCA1/SR-B1 cholesterol transporters were assessed. AA and DG each induced mild, largely sublethal ATP depletion injury. Each also caused significant HMGCR increments and SR-B1 decrements and left ABCA1 intact. In contrast, only AA increased the LDL-R, and only AA evoked a cholesterol-loading state (∼25% ↑). One-half of this increase was statin inhibitable, and one-half could be blocked by serum deletion, implying that both synthetic and nonsynthetic (e.g., LDL-R transport) pathways were involved. The AA-induced HMGCR and LDL-R protein changes were paralleled by their mRNAs, suggesting the presence of altered transcriptional events. We conclude that 1) sublethal ATP depletion, whether induced by mitochondrial or glycolytic blockade, can upregulate HMGCR and decrease SR-B1, and these changes represent a previously unrecognized ATP depletion “phenotype”; 2) mitochondrial blockade can also upregulate the LDL-R and evoke a cholesterol-loading state; 3) the latter likely occurs via synthetic and transport pathways; and 4) the mitochondrion may be a critical, and previously unrecognized, determinant of postinjury cell cholesterol homeostasis, potentially by impacting the LDL-R.

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Horton, J. D., J. A. Cuthbert, and D. K. Spady. "Dietary fatty acids regulate hepatic low density lipoprotein (LDL) transport by altering LDL receptor protein and mRNA levels." Journal of Clinical Investigation 92, no. 2 (August 1, 1993): 743–49. http://dx.doi.org/10.1172/jci116645.

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Journal articles on the topic 'LDL transport'

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